Unlike other tissue which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which was early characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normally, high glutamate concentrations are maintained inside cells of the CNS by energy-dependent transport systems, but high concentrations are not allowed in the extracellular compartment where glutamate can exert excitotoxic action at excitatory synaptic receptors. Under low energy conditions such as hypoglycemia, hypoxia or ischemia, cells release glutamate and, because of the energy deficiency, the transport systems are unable to move glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamate receptors, also known as excitatory amino acid (EAA) receptors, are of three types, each being named after the EAA glutamate analogue which selectively excites them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS). Glutamate is believed to be a mixed (broad spectrum) agonist capable of binding to and exciting all three EAA receptor types.
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia which occurs in conditions such as stroke, cardiac arrest or perinatal asphyxia.
Phencyclidine (PCP) and the PCP-like compound ketamine have been found to reduce selectively the excitatory effects of NMDA as compared to KA and QUIS [Anis, N. A. et al, "The Dissociative Anaesthetics, Ketamine and Phencyclidine, Selectively Reduce Excitation of Central Mammalian Neurones by N-Methyl-Aspartate", Br. J. Pharmacol., 79, 565 (1983)]. Blocking of NMA neurotoxicity by PCP and ketamine has been demonstrated [J. W. Olney et al., "The Anti-Excitotoxic Effects of Certain Anesthetics, Analgesics and Sedative-Hypnotics," Neuroscience Letters, 68, 29-34 (1986)].
A correlation has been found between the PCP binding effects of some PCP-derivative stereoisomers and NMDA antagonism. For example, the stereoselective effects of cis-N-(1-phenyl-4-methylcyclohexyl)piperidine and (+)-1-(1-phenylcyclohexyl)-3-methylpiperidine [(+)-PCMP] over each of their corresponding isomer counterparts in reducing the excitatory action of NMDA have been confirmed in binding and behavioral data [S. D. Berry et al, "Stereoselective Effects of Two Phencyclidine Derivatives on N-Methylaspartate Excitation of Spinal Neurones in the Cat and Rat", Eur. J. Pharm., 96, 261-267 (1983)]. Also, the compound (+)-PCMP has been found to be a potent inhibitor of the specific binding of [.sup.3 H]PCP to rat cerebral cortical membranes [M. E. Goldman et al, "Differentiation of .sup.3 H]Phencyclidine and (+)-[.sup.3 H]SKF-10,047 Binding Sites in Rat Cerebral Cortex", FEBS Lett., 170, 333-336 (1985)]. It has also been shown that PCP and NMA receptors are co-localized throughout much of the mammalian forebrain [W. Maragos et al, "High Correlation Between the Localization of [.sup.3 H]TCP Binding and NMDA Receptors", Eur. J. Pharmacol., 123, 173-174 (1986)].
Various compounds, such as arylcycloalkylamines, benzomorphans and 1,3-dioxolanes, have been identified as potential PCP receptor agonists on the basis of their ability to displace PCP receptor ligands in binding assays [R. Quirion, "Phencyclidine (Angel Dust)/Sigma `Opiate` Receptor: Visualization by Tritium-Sensitive Film", Proc. Nat'l. Acad. Sci. U.S.A., 78, 5881 (1981)]. These same agents have been shown to antagonize certain biological effects of NMA such as NMA-induced release of transmitter from striatal brain tissue [L. D. Snell et al, "Antagonism of N-Methyl-D-Aspartate-Induced Transmitter Release In The Rat Striatum By Phencyclidine-Like Drugs And Its Relationship To Turning Behavior", J. Pharmacol. Exp. Ther., 235, 50-56, (1985)].
The compound MK-801 {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate)} has been found to be a potent, selective non-competitive antagonist of the N-methyl-D-aspartate receptor site [E. H. F. Wong et al, "The Anticonvulsant MK-801 Is A Potent N-Methyl-D-Aspartate Antagonist", Proc. Nat'l. Acad. Sci U.S.A., Vol. 83, pp. 7104-7108 (Sept. (1986)].
Well-known competitive NMA antagonists, such as D-.alpha.-amino-5-phosphonopentanoate, are capable of effectively blocking the excitotoxic effects of NMA. But such compounds show little therapeutic promise in treatment or prevention of ischemic brain damage because these compounds do not penetrate the blood-brain barrier.
Compounds such as procyclidine, biperiden and trihexyphenidyl are known to have anti-cholinergic actions and have been identified for treatment of Parkinsonism. Such compounds are known to ameliorate the muscle rigidity and akinesia associated with Parkinsonism and extrapyramidal symptoms associated with neuroleptic drug treatment [L. S. Goodman et al, The Pharmacological Basis of Therapeutics, 5th Edn., Macmillan (1975)].
Aryl-cycloalkyl-alkanolamine compounds and derivatives have been described for various pharmaceutical purposes. For example, the compound .alpha.-bicyclo[2.2.1]hept-5-en-2-yl-.alpha.-phenyl-1-piperidinepropanol, commonly known as biperiden, has been studied for its mood altering effects [W. W. Fleischhacker et al, J. Affective Disorder, 12 (2), 153-157 (1987)], and for its interaction with brain muscarinic cholinoceptors [E. K. G. Syvalahti et al, Pharmacol. Toxicol. (Copenhagen), 60 (1), 66-69 (1987)]. The hydrochloride salt of biperiden has been studied for its interaction with nicotine and oxotremorine in rat diaphragm [M. Das et al, Toxicol. Appl. Pharmacol., 39 (1), 149-152 (1977). U.S. Pat. No. 2,891,890 describes the compound .alpha.-cyclohexyl-.alpha.-phenyl-1-pyrrolidinepropanol hydrochloride and its free base, commonly known as procyclidine, which is an anti-cholinergic compound having anti-convulsant properties. U.S. Pat. No. 4,031,245 mentions the compound .alpha.-cyclopropyl-.alpha.-[3-(trifluoromethyl)phenyl]-1-piperidinepropan ol and its hydrochloride derivative in a description of alkenyl and alkanylamines for treating depression. U.S. Pat. No. 3,553,225 mentions the compound .alpha.-phenyl-.alpha.-tricyclo[3,3,1,13,7]dec-1-yl-1-piperidinebutanol in a description of adamantane derivatives as tranquilizers. West German Offen. No. 1,951,614, in a description of benzyl alcohol derivatives having sedative and ulcer-preventing properties, mentions the compounds a-(4-amino-3,5-dibromophenyl)-a-cyclohexyl-1-piperidinebutanol, .alpha.-(4-amino-3-chlorophenyl)-.alpha.-cyclohexylhexahydro-1H-azepine-1- butanol, .alpha.-(4-amino-3,5-dichlorophenyl)-.alpha.-cyclohexylhexahydro-1H-azepin e-1-butanol and .alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-cyclohexyl-1,8,8-trimethyl-3-a zabicyclo[3,2,1]octane-3-butanol. The compound .alpha.-[1,1'-biphenyl]-4-yl-o-cyclohexyl-1piperidinepropanol hydrochloride was mentioned in a study of the potential analgetic activity of some reduced biphenyl Mannich bases [N. Mann et al, Arch. Pharm. (Weinheim, Ger.), 309 (4), 320-325 (1976)]. The compound .alpha.-phenyl-.alpha.-tricyclo[2.2.1.02,6hept-3-yl-1-piperidinepropanol hydrochloride, commonly known as triperiden, is a known anti-Parkinsonism agent also having anti-viral properties [C. Schroeder et al, Antiviral Res., Suppl. 1, 95-99 (1985)]. The compound .alpha.-cyclohexyl-.alpha.-phenyl-1-piperidinepropanol, commonly known as trihexyphenidy], is a known anti-Parkinsonian which has been studied for its effects in schizophrenic patients [A. Hitri et al, Psychopharmacol. Bull., 23 (1) 33-37 (1987) and for its effects on memory in elderly patients [J. P. McEvoy et al, Psychopharmacol. Bull., 23 (1), 30-32 (1987)].